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Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5.
Molecules. 2020 Jun 15; 25(12)M

Abstract

Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases. They regulate many physiological processes and play important roles in inflammation, diabetes, cancers, and neurodegeneration diseases. Sirtuin inhibitors have potential applications in the treatment of neurodegenerative diseases and various cancers. Herein, we identified new sirtuin inhibitors based on the scaffold of 8-mercapto-3,7-dihydro-1H-purine-2,6-dione. To elucidate the inhibitory mechanism, the binding modes of the inhibitors in SIRT3 were established by molecular docking, showing that the inhibitors occupy the acetyl lysine binding site and interact with SIRT3, mainly through hydrophobic interactions. The interactions were validated by site-directed mutagenesis of SIRT3 and structure-activity relationship analysis of the inhibitors. Consistently, enzyme kinetic assays and microscale thermophoresis showed that these compounds are competitive inhibitors to the acetyl substrate, and mix-type inhibitors to NAD+. Furthermore, we demonstrated that the compounds are potent SIRT1/2/3/5 pan-inhibitors. This study provides novel hits for developing more potent sirtuin inhibitors.

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Authors+Show Affiliations

Han H
Department of Pharmacology III, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China. College of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.
Li C
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
Li M
School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Yang L
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
Zhao S
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
Wang Z
School of Basic Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
Liu H
Department of Medicinal Chemistry, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China.
Liu D
Department of Pharmacology III, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu-Chong-Zhi Road, Shanghai 201203, China. College of Pharmacy, University of Chinese Academy of Sciences, No.19A Yuquan Road, Beijing 100049, China.

MeSH

Binding SitesDrug DesignHumansKineticsMolecular Docking SimulationMolecular StructureSirtuin 1Sirtuin 2Sirtuin 3SirtuinsStructure-Activity RelationshipTheophylline

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32549218

Citation

Han, Haozhen, et al. "Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5." Molecules (Basel, Switzerland), vol. 25, no. 12, 2020.
Han H, Li C, Li M, et al. Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5. Molecules. 2020;25(12).
Han, H., Li, C., Li, M., Yang, L., Zhao, S., Wang, Z., Liu, H., & Liu, D. (2020). Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5. Molecules (Basel, Switzerland), 25(12). https://doi.org/10.3390/molecules25122755
Han H, et al. Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5. Molecules. 2020 Jun 15;25(12) PubMed PMID: 32549218.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Design, Synthesis, and Biological Evaluation of 8-Mercapto-3,7-Dihydro-1H-Purine-2,6-Diones as Potent Inhibitors of SIRT1, SIRT2, SIRT3, and SIRT5. AU - Han,Haozhen, AU - Li,Chunpu, AU - Li,Man, AU - Yang,Lisheng, AU - Zhao,Sen, AU - Wang,Zhifei, AU - Liu,Hong, AU - Liu,Dongxiang, Y1 - 2020/06/15/ PY - 2020/05/06/received PY - 2020/06/05/revised PY - 2020/06/06/accepted PY - 2020/6/19/entrez PY - 2020/6/19/pubmed PY - 2021/2/17/medline KW - deacetylase KW - inhibitor KW - sirtuins KW - structure–activity relationship JF - Molecules (Basel, Switzerland) JO - Molecules VL - 25 IS - 12 N2 - Sirtuins (SIRT1-7) are a family of NAD+-dependent deacetylases. They regulate many physiological processes and play important roles in inflammation, diabetes, cancers, and neurodegeneration diseases. Sirtuin inhibitors have potential applications in the treatment of neurodegenerative diseases and various cancers. Herein, we identified new sirtuin inhibitors based on the scaffold of 8-mercapto-3,7-dihydro-1H-purine-2,6-dione. To elucidate the inhibitory mechanism, the binding modes of the inhibitors in SIRT3 were established by molecular docking, showing that the inhibitors occupy the acetyl lysine binding site and interact with SIRT3, mainly through hydrophobic interactions. The interactions were validated by site-directed mutagenesis of SIRT3 and structure-activity relationship analysis of the inhibitors. Consistently, enzyme kinetic assays and microscale thermophoresis showed that these compounds are competitive inhibitors to the acetyl substrate, and mix-type inhibitors to NAD+. Furthermore, we demonstrated that the compounds are potent SIRT1/2/3/5 pan-inhibitors. This study provides novel hits for developing more potent sirtuin inhibitors. SN - 1420-3049 UR - https://www.unboundmedicine.com/medline/citation/32549218/Design_Synthesis_and_Biological_Evaluation_of_8_Mercapto_37_Dihydro_1H_Purine_26_Diones_as_Potent_Inhibitors_of_SIRT1_SIRT2_SIRT3_and_SIRT5_ DB - PRIME DP - Unbound Medicine ER -